Parkinson's disease is a disabling and common neurodegenerative disease involving complex environmental and genetic interactions. Mutations in a few genes have been associated with rare familial cases with early onset, but emerging evidence suggests genetic factors also play a role in late onset sporadic PD. Our exciting preliminary findings describe a novel locus, PARK10, associated with late onset PD in Iceland. The proposed collaborative research project between deCODE genetics and Emory University investigators now capitalizes on this finding to extend the search for the responsible gene in Icelanders and in a large PD research and clinical center in Atlanta. Aim 1: deCODE will refine the location of the gene within this locus using DNA from both the Iceland and US populations, including haplotype analysis and a search for mutations in the Emory clinical material. Aim 2: Support for candidate genes within the locus will be pursued by studying the localization and expression of the encoded proteins using neuropathological and biochemical approaches. Aim 3: Alterations in the lead gene products will be investigated in experimental models of parkinsonism using rotenone treated, genetically modified mice. Together, these studies will identify the gene responsible for late onset PD in Iceland and determine its significance in Americans. Moreover, the results will provide insights into the biological significance of the gene product and its association with the pathology in postmortem human brain, and how it may be interact with environmental toxins in experimental models.